Editorial [Hot Topic:Novel Targets in Cancer Therapy(Guest Editor: Debabrata Banerjee)]

Novel Targets in Cancer Therapy In this special issue six articles on current developments in the field of cancer research with special emphasis on novel approaches and or novel targets in cancer chemotherapy are presented. These include identification of novel targets in breast cancer such as the bone marrow microenvironment and the interaction with subsets of tumor cells including tumor stem cells (see article by Rameshwar), the notch signaling pathway (see article by Purow BJ), epigenetics (Humeniuk et al.), novel ideas regarding targeting the immune system for cancer immunotherapy (see Chaudhury et al.), targeting the tumor stromal interaction (article by Anton and Glod) and lastly targeting the tumor initiating cells or tumor stem cells (see article by Bansal and Banerjee). Rameshwar discusses a new way of thinking for identifying the breast cancer stem cells and other subsets in bone marrow. Following entry of breast cancer cells in the marrow, it is proposed that the first step involves formation of gap junctional intercellular communication between cancer cells and stromal cells close to the endosteum. An understanding of the mechanisms by which cancer cell subsets interact with other cells of the bone marrow could lead to an understanding of cancer behavior in bone marrow and may lead to identification of novel therapeutic targets. Chaudhury et al. propose that the immunosuppressive tumor environment can be altered to become immune activating, thus facilitating the infiltration of myeloid and lymphoid cells that can act in concert leading to tumor regression. In this regard, immunotherapeutic approaches such as DNA vaccines, dendritic cell based vaccines, HSP based vaccines and gene transfer technology, are being developed and further refined to overcome their inherent limitations. They argue that careful evaluation of the suppressive nature of the tumor microenvironment accompanied by qualitative and quantitative measurements of lymphocyte responses in patients may lead to development of more meaningful therapeutic strategies. Combined with development of advanced genetic technologies and continuous identification of novel tumor antigens, the field of cancer immunotherapy is poised to make major advances. The Notch signaling pathway has been found to play central roles in humans in stem cell maintenance, cell fate decisions, and in cancer as well. Notch family members are now being recognized as oncogenes in an ever-increasing number of cancers making them attractive therapeutic targets. Purow makes the case that although significant progress has been made in dissecting the complex workings of this signaling pathway, there are very limited options available for clinical use of Notch inhibitors. The review addresses current state-of-the-art, newer notch targeting agents in the pipeline, and potential strategies for use of future Notch inhibitors in the clinic as anticancer agents. Humeniuk et.al. propose that epigenetic modifications can be transmitted to the next generation and used to turn off and/or on certain genes or pathways that may confer survival benefit to a cancer cell. As the epigenetic changes are readily reversible, strong arguments can be made in favor of “epigenetic therapy”. They are quick to point out that a potential problem in this therapeutic approach is the lack of specificity as epigenetic modifications are used by both normal and cancer cells to regulate expression of various genes. They refer to ongoing studies to identify genes that are differentially expressed in cancer cells vs. normal cells are providing valuable information about molecular targets for epigenetic therapy. Humeniuk et al. summarize some of these studies and discus the differences between conventional and epigenetic therapy utilizing epigenetic drugs like DNA methyltransferase inhibitors or histone deacetylase inhibitors. Current thoughts on the future of epigenetic therapy are also discussed. It is now recognized that the stroma plays a role in processes such as nutritional support, the removal of waste products, and the creation of a barrier regulating the exchange of fluids, gases, and cells. The stroma provides support with growth factors and cytokines and promotes angiogenesis, tissue invasion, and metastasis. More recently, it has become evident that the stroma provides a chemoresistant capability to the tumor, preventing chemotherapeutics from reaching their target. Anton and Glod discuss the recent developments in targeting the various players involved in the tumor stroma interactions and argue that future development of more specific targets will depend upon further characterization of the cellular and molecular interactions in the tumor microenvironment.